Type of Fluid Resuscitation Matters in Patients With Sepsis

Joanna Broder

June 27, 2012

June 27, 2012 — Despite the fact that hydroxyethyl starch (HES) 130/0.4 is used frequently for fluid resuscitation in intensive care units, it is unknown how safe and effective it is for patients with severe sepsis.

That is according to Anders Perner, MD, PhD, of the Department of Intensive Care, Center of Clinical Intervention Research at Copenhagen University Hospital in Denmark, and colleagues, in a new study, the results of which are adding to a growing body of research that this type of treatment may do more harm than good.

According to the study, published online June 27 by the New England Journal of Medicine, patients who received fluid resuscitation with HES 130/0.4 had an increased risk for death and dependency on renal replacement therapy at 90 days post-resuscitation when compared with patients who received fluid resuscitation with Ringer’s acetate.

"I think the findings are not equivocal. It basically says that the stuff is bad for your kidneys," said Clifford Deutschman, MD, a professor of anesthesiology and critical care at the Perelman School of Medicine at the University of Pennsylvania.

The important point for critical care doctors is that HES is one more thing that "we relied on that doesn't work or that we have to be very careful about using," he added in an interview with Medscape Medical News. Dr. Deutschman was not involved with the NEJM study.

HES, a fluid used for resuscitation, is marketed under the names Hespan® or Hextend®. Hetastarch® is another "nickname" for HES, said Dr. Deutschman, who is also president of the Society of Critical Care Medicine.

HES is a colloid. Colloids are large particles that either are proteins (albumin) or are designed to act like proteins that are a normal part of the blood, Dr. Deutschman said in an email.

"Because of their size, colloids tend to stay in the blood stream and to hold water with them," he wrote.

Another option for fluid resuscitation in sepsis is crystalloids, or salt solutions. "Because these ions are smaller than colloids they can 'leak' out of the blood stream and into the tissues, taking water with them and causing edema," he noted.

However, recent research has suggested that molecules like HES can be harmful. A study published in 2008, the Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis (VISEP Trial), was designed to examine both the use of a slightly different type of starch for the purposes of resuscitation and in intensive insulin therapy for tight glucose control.

"They stopped the HES arm of the study early because of an increased incidence of renal failure, renal insufficiency in the patients getting the starch," Dr. Deutschman said.

HES is structured slightly differently from the one used in the VISEP study, Dr. Deutschman said, so the research community thought the outcome of this trial might be different from that of the VISEP trial.

This study seems to have proved otherwise.

In the multicenter, parallel-group, blinded trial, 804 patients with severe sepsis were randomly assigned to receive fluid resuscitation in the intensive care unit either by way of 6% HES 130/0.4 or with Ringer's acetate, at a dose of up to 33 mL per kilogram of ideal body weight per day.

Patients were screened at 26 general intensive care units in 13 university and 13 nonuniversity hospitals between December 23, 2009, and November 15, 2011, in Denmark, Norway, Finland, and Iceland. Ultimately, 798 people were included in the modified intention-to-treat population.

The 2 intervention groups had similar baseline characteristics.

Results showed that at 90 days post-randomization, 51% of the group assigned to HES 130/0.4 had died (201 of 398 patients) compared with 43% of the group assigned to Ringer’s acetate (172 of 400 patients; relative risk [RR], 1.17; 95% confidence interval [CI], 1.01 to 1.36; P = .03). One patient in each group had end-stage kidney failure.

Also within the 90-day period, 22% of patients assigned to HES (87 patients) received treatment for renal replacement vs 16% (65 patients) in the Ringer’s acetate group (RR, 1.35; 95% CI, 1.01 to 1.80, P = .04).

The risk for severe bleeding within the 90-day period was also higher for the HES group (10%, or 38 patients) as compared with the Ringer’s group (6%, or 25 patients; RR, 1.52; 95% CI, 0.94 to 2.48; P = .09).

Dr. Deutschman said that there are still a lot of questions about HES. It is used extensively and has a "pretty substantial" market, he explained. Years ago, there were concerns about using the protein albumin to treat severe sepsis, so doctors started using HES instead.

"It turns out, I think, that the concerns about albumin are misplaced and the faith in this particular compound is probably an issue."

He said nobody knows the precise mechanism of how HES may lead to kidney failure.

"My guess, and it's completely a guess, is that when it gets into the kidneys, it just sort of clogs things up and prevents adequate flow of fluid through and adequate creation of urine," Dr. Deutschman said.

He noted that the study was "well conducted. . . . It will change some of the recommendations and it's going to change the way a lot of people treat patients with sepsis."

But Dr. Deutschman tempered his assessment. "The downside of any of these big trials is it doesn't mean that the HES is bad for everybody and it doesn't mean it's dangerous for everybody.

"You know there might be a group of patients buried within this big group of people that made up the HES group that actually do benefit from using this, but it's not something that's valuable -- blanket across the board -- to every septic patient."

Dr. Perner reports receiving grant support from Fresenius Kabi. He has disclosed no relevant financial relationships. Dr. Deutschman disclosed that he has received grants from the National Institutes of Health.

N Engl J Med. Published online June 27, 2012. Abstract


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